DESCRIPTION: (Applicant's Abstract) The alarming increase in cocaine abuse that has occurred over the last decade has been reflected in the prevalence of cocaine use during pregnancy, estimated to be as high as 8% to 30% in some regions. Consequently, there is now a sizable population of children that have been exposed to the effects of cocaine during the initial stages of their development. Cocaine use during pregnancy appears to be associated with a variety of neurobehavioral abnormalities in the progeny. While some of the effects of fetal exposure to cocaine appear transiently in neonates, there are indications that some long-lasting deficits may occur. In particular, the incidence of attention deficit hyperactivity disorder (ADDH) appears to be markedly increased following prenatal exposure to cocaine. While these clinical studies are extremely suggestive of harmful effects of gestational exposure to cocaine, controlled studies in laboratory animals are needed in order to understand more fully the effect that cocaine use during pregnancy has on the offspring, and to find ways of reversing the deficit. The overall hypothesis of this proposal, for which strong preliminary data are presented, is that prenatal exposure to cocaine can disturb the function of the dopamine input to the prefrontal cortex of the progeny, and that such a deficit is reflected in cognitive deficits that are most apparent under stressful conditions. We propose to pursue this hypothesis using sensitive biochemical and behavioral measurements to study the offspring of rats given cocaine during pregnancy. Biochemical techniques will include in vitro and in vivo measures of neuronal activity pre- and postsynaptic to the dopaminergic terminals in the prefrontal cortex. Stress-induced alterations in behavioral measures of spatial working memory will be assessed by performance in a delayed alternation task. Stress will be induced by exposing rats to the effects of either an anxiogenic B-carboline drug or a stressful olfactory cue. Abnormalities induced by prenatal exposure to cocaine will be investigated at 3 postnatal ages. The effect will be pursued in both male and female progeny, as our preliminary data indicate some gender specific effects of gestational exposure to cocaine. While we anticipate that such studies will provide valuable scientific insights into the impact of prenatal cocaine on the function of the prefrontal cortex, we are hopeful that the studies in which the deficits are reversed pharmacologically will have positive social and economical repercussions by providing leads to the logical choices of drugs, and development of new drugs, to treat the detrimental effects of prenatal cocaine exposure.